Gender differences have been known to occur in a variety of autoimmune diseases for decades, with females being more susceptible in most cases. Gender differences in disease susceptibility have been shown to be due at least in part to the effects of sex hormones. However, an influence of sex hormones on autoimmune disease susceptibility does not preclude an additional role for sex chromosomes in the gender differences that have been observed. The goal of this proposal will be to determine whether sex chromosomes play this additional role. To determine this, we will utilize a prototypic autoimmune disease model, experimental autoimmune encephalomyelitis (EAE) in SJL mice. The gender difference in EAE in SJL mice has been previously characterized, with females being more susceptible and more severely affected as compared to males. We will use this model to distinguish between the following two possibilities: (1) gender differences in the susceptibility and severity of EAE in SJL mice are due to effects of sex hormones only (with no influence of sex chromosomes) versus (2) gender differences in the susceptibility and severity of EAE in SJL mice are due to both sex hormones and sex chromosomes. We will distinguish between these two possibilities by creating uniquely informative mice. Mice which have a separation of sex hormone phenotype (male versus female) and sex chromosome genotype (XX versus XY) will be bred onto the SJL background, the background in which the gender differences in immune measures relevant to the development of EAE have been well characterized (pro/anti-inflammatory cytokine ratio, encephalitogenicity, disease severity). Experiments using these uniquely informative mice will then determine whether differences in these same immune measures exist in mice, which share a common sex hormone phenotype but have a different sex chromosome genotype. If immune measures are no different between genotypes (XX vs. XY) within a given phenotype, then we will conclude that gender differences in immune measures are due to sex hormones only and not sex chromosomes. On the other hand, if immune measures differ between genotypes (XX vs. XY) within a given phenotype, we will conclude that gender differences in immune measures are due to both sex hormones and sex chromosomes.